The primary objectives of this proposal include: a) To evaluate the induction and reversal of organic nitrate tolerance (in vitro and in vivo); b) to determine the mechanism of tolerance development to organic nitrates as well as other vasodepressor agents; c) to investigate the mechanism by which organic nitrates and other direct acting spasmolytic compounds relax smooth muscle; and d) to synthesize and test nitrate high affinity analogs designed to react with and bind to nitrate receptors. Bibliographic references: P. Needleman. "Biotransformation of Organic nitrates", Chapter 5 in Organic Nitrates, Handbook of Experimental Pharmacology, Vol. 40 Springer-Verlag, Ed. P. Needleman, Berlin 57-96 (1975). P. Needleman and E.M. Johnson, Jr. "The Pharmacological and Biochemical Interaction of Organic Nitrates with Sulfydryls: Possible Correlation with the Mechanism for Tolerance Development, Vasodilation and Mitochondrial and Enzyme Reactions", Chapter 6 in Organic Nitrates, Handbook of Experimental Pharmacology, Vol. 40, Springer-Verlag, Editor, P. Needleman, Berlin 97-114 (1975).